Binding of an X-Specific Condensin Correlates with a Reduction in Active Histone Modifications at Gene Regulatory Elements

Condensins are evolutionarily conserved protein complexes that are required for chromosome segregation during cell division and genome organization during interphase. In Caenorhabditis elegans, a specialized condensin, which forms the core of the dosage compensation complex (DCC), binds to and represses X chromosome transcription. Here, we analyzed DCC localization and the effect of DCC depletion on histone modifications, transcription factor binding, and gene expression using chromatin immunoprecipitation sequencing and mRNA sequencing. Across the X, the DCC accumulates at accessible gene regulatory sites in active chromatin and not heterochromatin. The DCC is required for reducing the levels of activating histone modifications, including H3K4me3 and H3K27ac, but not repressive modification H3K9me3. In X-to-autosome fusion chromosomes, DCC spreading into the autosomal sequences locally reduces gene expression, thus establishing a direct link between DCC binding and repression. Together, our results indicate that DCC-mediated transcription repression is associated with a reduction in the activity of X chromosomal gene regulatory elements.

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Binding of an X-specific condensin correlates with a reduction in active histone modifications at gene regulatory elements

10.1101/516419 ◽

2019 ◽

Author(s):

Lena Annika Street ◽

Ana Karina Morao ◽

Lara Heermans Winterkorn ◽

Chen-Yu Jiao ◽

Sarah Elizabeth Albritton ◽

...

Keyword(s):

Gene Expression ◽

Histone Modifications ◽

Protein Complexes ◽

Regulatory Elements ◽

Chromosomal Gene ◽

Direct Link ◽

C Elegans ◽

Evolutionarily Conserved ◽

Gene Regulatory Elements ◽

Gene Regulatory

ABSTRACTCondensins are evolutionarily conserved protein complexes that are required for chromosome segregation during cell division and genome organization during interphase. In C. elegans,, a specialized condensin, which forms the core of the dosage compensation complex (DCC), binds to and represses X chromosome transcription. Here, we analyzed DCC localization and the effect of DCC depletion on histone modifications, transcription factor binding, and gene expression using ChIP-seq and mRNA-seq. Across the X, DCC accumulates at accessible gene regulatory sites in active chromatin and not heterochromatin. DCC is required for reducing the levels of activating histone modifications, including H3K4me3 and H3K27ac, but not repressive modification H3K9me3. In X-to-autosome fusion chromosomes, DCC spreading into the autosomal sequences locally reduces gene expression, thus establishing a direct link between DCC binding and repression. Together, our results indicate that DCC-mediated transcription repression is associated with a reduction in the activity of X chromosomal gene regulatory elements.SUMMARYCondensins are evolutionarily conserved protein complexes that mediate chromosome condensation during cell division and have been implicated in gene regulation during interphase. Here, we analyzed the gene regulatory role of an X-specific condensin (DCC) in C. elegans, by measuring its effect on histone modifications associated with transcription regulation. We found that in X-to-autosome fusion chromosomes, DCC spreading into autosomal sequences locally reduces gene expression, establishing a direct link between DCC binding and repression. DCC is required for reduced levels of histone modifications associated with transcription activation at X chromosomal promoters and enhancers. These results are consistent with a model whereby DCC binding directly or indirectly results in a reduction in the activity of X chromosomal gene regulatory elements through specific activating histone modifications.

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BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome

10.1101/2020.11.13.381251 ◽

2020 ◽

Author(s):

Nadezda A. Fursova ◽

Anne H. Turberfield ◽

Neil P. Blackledge ◽

Emma L. Findlater ◽

Anna Lastuvkova ◽

...

Keyword(s):

Gene Expression ◽

Histone Modifications ◽

Transcription Initiation ◽

Target Genes ◽

Regulatory Elements ◽

Polycomb Group ◽

Gene Promoters ◽

Histone H2a ◽

Gene Regulatory Elements ◽

Gene Regulatory

AbstractHistone-modifying systems play fundamental roles in gene regulation and the development of multicellular organisms. Histone modifications that are enriched at gene regulatory elements have been heavily studied, but the function of modifications that are found more broadly throughout the genome remains poorly understood. This is exemplified by histone H2A mono-ubiquitylation (H2AK119ub1) which is enriched at Polycomb-repressed gene promoters, but also covers the genome at lower levels. Here, using inducible genetic perturbations and quantitative genomics, we discover that the BAP1 deubiquitylase plays an essential role in constraining H2AK119ub1 throughout the genome. Removal of BAP1 leads to pervasive accumulation of H2AK119ub1, which causes widespread reductions in gene expression. We show that elevated H2AK119ub1 represses gene expression by counteracting transcription initiation from gene regulatory elements, causing reductions in transcription-associated histone modifications. Furthermore, failure to constrain pervasive H2AK119ub1 compromises Polycomb complex occupancy at a subset of Polycomb target genes leading to their derepression, therefore explaining the original genetic characterisation of BAP1 as a Polycomb group gene. Together, these observations reveal that the transcriptional potential of the genome can be modulated by regulating the levels of a pervasive histone modification, without the need for elaborate gene-specific targeting mechanisms.

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Gene-regulatory elements may change the amount, timing, or location of gene expression, cis-Regulation therapy platforms might become a gene therapy to treat many genetic diseases

10.31219/osf.io/xc5a2 ◽

2021 ◽

Author(s):

Moataz Dowaidar

Keyword(s):

Gene Expression ◽

Genetic Diseases ◽

Regulatory Elements ◽

Tissue Type ◽

Gene Promoters ◽

Expression Levels ◽

Cis Regulation ◽

Gene Regulatory Elements ◽

Gene Regulatory ◽

Gene Expression Levels

Changes in gene expression levels above or below a particular threshold may have a dramatic impact on phenotypes, leading to a wide spectrum of human illnesses. Gene-regulatory elements, also known as cis-regulatory elements (CREs), may change the amount, timing, or location (cell/tissue type) of gene expression, whereas mutations in a gene's coding sequence may result in lower or higher gene expression levels resulting in protein loss or gain. Loss-of-function mutations in both genes produce recessive human illness, while haploinsufficient mutations in 65 genes are also known to be deleterious due to function gain, according to the ClinVar1 and ClinGen3 databases. CREs are promoters living near to a gene's transcription start site and switching it on at predefined times, places, and levels. Other distal CREs, like enhancers and silencers, are temporal and tissue-specific control promoters. Enhancers activate promoters, commonly referred to as "promoters," whereas silencers turn them off. Insulators also restrict promiscuous interactions between enhancers and gene promoters. Systematic genomic approaches can help understand the cis-regulatory circuitry of gene expression by highly detecting and functionally defining these CREs. This includes the new use of CRISPR–CRISPR-associated protein 9 (CRISPR–Cas9) and other editing approaches to discover CREs. Cis-Regulation therapy (CRT) provides many promises to heal human ailments. CRT may be used to upregulate or downregulate disease-causing genes due to lower or higher levels of expression, and it may also be used to precisely adjust the expression of genes that assist in alleviating disease features. CRT may employ proteins that generate epigenetic modifications like methylation, histone modification, or gene expression regulation looping. Weighing CRT's advantages and downsides against alternative treatment methods is crucial. CRT platforms might become a practical technique to treat many genetic diseases that now lack treatment alternatives if academics, patient communities, clinicians, regulators and industry work together.

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Scavenger receptor A gene regulatory elements target gene expression to macrophages and to foam cells of atherosclerotic lesions.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.92.12.5391 ◽

1995 ◽

Vol 92 (12) ◽

pp. 5391-5395 ◽

Cited By ~ 84

Author(s):

A. Horvai ◽

W. Palinski ◽

H. Wu ◽

K. S. Moulton ◽

K. Kalla ◽

...

Keyword(s):

Gene Expression ◽

Target Gene ◽

Scavenger Receptor ◽

Foam Cells ◽

Regulatory Elements ◽

Target Gene Expression ◽

Atherosclerotic Lesions ◽

Gene Regulatory Elements ◽

Scavenger Receptor A ◽

Gene Regulatory

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1273. High Level, Erythroid Lineage-Specific Gene Expression Using Globin Gene Regulatory Elements Following Lentiviral Vector-Mediated Gene Transfer into Primitive Human and Murine Hematopoietic Cells

Molecular Therapy ◽

10.1016/s1525-0016(16)44103-1 ◽

2002 ◽

Vol 5 (5) ◽

pp. S415

Keyword(s):

Gene Expression ◽

Gene Transfer ◽

Lentiviral Vector ◽

Globin Gene ◽

Regulatory Elements ◽

Specific Gene ◽

Gene Regulatory Elements ◽

Gene Regulatory ◽

High Level ◽

Lineage Specific Gene

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The interdependence of gene-regulatory elements and the 3D genome

The Journal of Cell Biology ◽

10.1083/jcb.201809040 ◽

2018 ◽

Vol 218 (1) ◽

pp. 12-26 ◽

Cited By ~ 20

Author(s):

Marit W. Vermunt ◽

Di Zhang ◽

Gerd A. Blobel

Keyword(s):

Gene Expression ◽

Molecular Mechanisms ◽

Regulatory Elements ◽

3D Genome ◽

Gene Positioning ◽

Transcriptional Changes ◽

Gene Regulatory Elements ◽

Chromatin Folding ◽

Gene Regulatory ◽

Relationship Of

Imaging studies, high-resolution chromatin conformation maps, and genome-wide occupancy data of architectural proteins have revealed that genome topology is tightly intertwined with gene expression. Cross-talk between gene-regulatory elements is often organized within insulated neighborhoods, and regulatory cues that induce transcriptional changes can reshape chromatin folding patterns and gene positioning within the nucleus. The cause–consequence relationship of genome architecture and gene expression is intricate, and its molecular mechanisms are under intense investigation. Here, we review the interdependency of transcription and genome organization with emphasis on enhancer–promoter contacts in gene regulation.

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Evaluation of combined gene regulatory elements for transcriptional targeting of suicide gene expression to malignant melanoma

Experimental Dermatology ◽

10.1111/j.0906-6705.2003.00093.x ◽

2003 ◽

Vol 12 (6) ◽

pp. 799-810 ◽

Cited By ~ 13

Author(s):

Heike Rothfels ◽

Annette Paschen ◽

Dirk Schadendorf

Keyword(s):

Gene Expression ◽

Malignant Melanoma ◽

Suicide Gene ◽

Regulatory Elements ◽

Transcriptional Targeting ◽

Gene Regulatory Elements ◽

Gene Regulatory

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Fast Detection of Differential Chromatin Domains with SCIDDO

10.1101/441766 ◽

2018 ◽

Author(s):

Peter Ebert ◽

Marcel H. Schulz

Keyword(s):

Histone Modifications ◽

Chromatin Immunoprecipitation ◽

Regulatory Elements ◽

Differential Analysis ◽

Chromatin Domains ◽

Chromatin Dynamics ◽

Fast Detection ◽

Genome Wide ◽

Chromatin Immunoprecipitation Sequencing

AbstractThe generation of genome-wide maps of histone modifications using chromatin immunoprecipitation sequencing (ChIP-seq) is a common approach to dissect the complexity of the epigenome. However, interpretation and differential analysis of histone ChIP-seq datasets remains challenging due to the genomic co-occurrence of several marks and their difference in genomic spread. Here we present SCIDDO, a fast statistical method for the detection of differential chromatin domains (DCDs) from chromatin state maps. DCD detection simplifies relevant tasks such as the characterization of chromatin changes in differentially expressed genes or the examination of chromatin dynamics at regulatory elements. SCIDDO is available at github.com/ptrebert/sciddo

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Distinct roles for CDK-Mediator in controlling Polycomb-dependent chromosomal interactions and priming genes for induction

10.1101/2021.11.04.467119 ◽

2021 ◽

Author(s):

Emilia Dimitrova ◽

Angelika Feldmann ◽

Robin H van der Weide ◽

Koen D Flach ◽

Anna Lastuvkova ◽

...

Keyword(s):

Gene Expression ◽

Gene Activation ◽

Embryonic Stem ◽

Regulatory Elements ◽

Gene Promoters ◽

Control Of Gene Expression ◽

Precise Control ◽

3D Genome ◽

Gene Regulatory Elements ◽

Gene Regulatory

Precise control of gene expression underpins normal development. This relies on mechanisms that enable communication between gene promoters and other regulatory elements. In embryonic stem cells (ESCs), the CDK-Mediator (CDK-MED) complex has been reported to physically link gene regulatory elements to enable gene expression and also prime genes for induction during differentiation. Here we discover that CDK-MED contributes little to 3D genome organisation in ESCs, but has a specific and essential role in controlling interactions between inactive gene regulatory elements bound by Polycomb repressive complexes (PRCs). These interactions are established by the canonical PRC1 (cPRC1) complex but rely on CDK-MED, which facilitates binding of cPRC1 to its target sites. Importantly, through separation of function experiments, we reveal that this collaboration between CDK-MED and cPRC1 in creating long-range interactions does not function to prime genes for induction during differentiation. Instead, we discover that priming relies on an interaction-independent mechanism whereby the CDK module supports core Mediator engagement with gene promoters to enable gene activation.

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